The series begins with Blossom's mother having left the family to pursue her own life and career and the family trying to adjust. Blossom's dad Nick is a session musician who was frequently between gigs and tours. Her oldest brother Anthony is a recovering alcoholic and drug addict. Joey (named Donny in the pilot episode), the other brother, is a fairly stereotypical "dumb jock", known for the drawn-out delivery of his catch phrase, "whoa".
Blossom's best friend Six LeMeure also plays a significant part in her life. Six, an especially fast talker, was best known for her tendency to ramble at an almost incoherent pace. Blossom also frequently received advice from famous celebrities in fantasy scenes, as Mr. T, Hugh Hefner, Phylicia Rashad and Will Smith all made guest appearances during the show's run.